Reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with aldehydes

Article abstract of DOI:10.1007/s10593-010-0604-0

The reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with a electrophilic reagent (anisaldehyde) was studied. It was shown that condensation of the latter with 2-(4-oxo-3,4-dihydro-2-quinazolyl)- and 2-(1H-benzo[d]imidazol-2-yl)-2-(tetrahydro-2-furanylidene)acetonitriles in the presence of secondary amines or acids takes place with elimination of the furan fragment and the formation of 3-aryl-2-(4-oxo-3,4-dihydro-2-quinazolinyl)- and 2-(1H-benzo[d]imidazol-2-yl)acrylo-nitriles.

Full text of DOI:10.1007/s10593-010-0604-0

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
REACTION OF 2-HETARYL-2-(TETRAHYDRO-
2-FURANYLIDENE)ACETONITRILES WITH ALDEHYDES
O. V. Khilya1*, Ya. V. Baglay1, and Yu. M. Volovenko1
The reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles with a electrophilic reagent
(anisaldehyde) was studied. It was shown that condensation of the latter with 2-(4-oxo-3,4-dihydro-
2-quinazolyl)- and 2-(1H-benzo[d]imidazol-2-yl)-2-(tetrahydro-2-furanylidene)acetonitriles in the
presence of secondary amines or acids takes place with elimination of the furan fragment and the
formation of 3-aryl-2-(4-oxo-3,4-dihydro-2-quinazolinyl)- and 2-(1H-benzo[d]imidazol-2-yl)acrylo-
nitriles.
Keywords: 2-(1H-benzo[d]imidazol-2-yl)acetonitrile, 2-(1H-benzo[d]imidazol-2-yl)-2-(tetrahydro-2-furan-
ylidene)acetonitriles, 2-(4-oxo-3,4-dihydro-2-quinazolinyl)acetonitrile, 2-(4-oxo-3,4-dihydro-2-quinazolyl)-
2-(tetrahydro-2-furanylidene)acetonitriles.
Earlier we described the synthesis of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles 1a [1-4] and
1b [2-4] starting from the corresponding 6-chloro-2-(hetarylidene)-3-oxohexanenitriles. It is known that the
reaction of (2Z)-(dihydro-2(3H)-furanylidene)acetonitriles with electrophilic reagents and with DMF dimethyl
acetal in particular takes place at position 3 of the furan system with the formation of 2-{3-[(E)-1-di-
methylaminomethylene]tetrahydro-2-furanylidene}acetonitrile [5, 6].
While continuing research into the reactions of furanylideneacetonitriles with electrophiles we studied
the reaction of 2-hetaryl-2-(tetrahydro-2-furanylidene)acetonitriles 1a,b with anisaldehyde (2).
The reaction of compounds 1a,b with the aldehyde 2 was conducted by heating in 2-propanol in the
presence of pyrrolidine. However, the expected condensation products 3a,b were not detected in the reaction
products. The structure of styrenes 4a,b was assigned to the products on the basis of data from elemental
1
analysis and H NMR, IR, and mass spectra. Further evidence for such a structure is the absence of a melting
point depression in a mixed melting test with a sample of compound 4a and the styrene obtained by the
previously described method [7].
1
Compounds 4a,b were obtained with yields of 78 and 84% respectively. In the H NMR spectra of the
styrenes 4a,b the signals of the aromatic protons are observed in the region of 7.1-8.2 ppm, and those of the
methine protons at 8.3-8.4 ppm.
_______
* To whom correspondence should be addressed, e-mail: olgakh@univ.kiev.ua.
1Taras Shevchenko Kiev National University, Kiev 01601, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1157-1161, August, 2010.
Original article submitted March 26, 2009.
934
0009-3122/10/4608-0934©2010 Springer Science+Business Media, Inc.

By realizing the reaction in the presence of various catalysts it was possible to establish that the
formation of compounds 4a,b can be catalyzed by both acids and bases. It was shown that the products 4a,b are
formed both in the presence of pyrrolidine and in the presence of hydrochloric acid. When p-toluenesulfonic
acid or triethylamine were used as catalysts the initial compounds 1a,b were isolated unchanged.
O
,
Het
N
H
CN
O
or HCl
O
2-PrOH
Het
2-PrOH
3
H
OMe
Het
+
CN
MeO
5a,b
CN
Het
or HCl
2
N
1a,b
H
CN
4a,b
OMe
O
N
H
N
NH
b
a
Het =
1–5
Het =
,
N
A similar transformation of 2-cyano-3-methylcrotonic ester in reaction with benzaldehyde in the
presence of piperidine, which catalyzes cleavage of the C=C bond of the crotonic fragment, was described in [8].
The obtained methyl cyanoacetate then condenses with the aldehyde. From the examined mechanism it follows
that the corresponding hetarylacetonitrile 5a,b must be formed in the reaction of compounds 1a,b with the
aldehyde 2 in the presence of pyrrolidine or HCl; by condensing with the anisaldehyde this will give the styrene
4a,b. When the reactions were carried out without the aldehyde the hetarylacetonitriles 5a,b were formed
[9, 10].
The obtained facts make it possible to suppose that the last transformation may correspond to the
following scheme of transformations:
O
H
+
O
+
H
O
H
Het
H2O
Het
+
Het
O
CN
H
OH
CN
H
H
CN
+
H
O
+
O
+
H
_
HO
H
O
Het
NH
O
H2O
OH
1a
Het
N
H
CN
1a
CN
CN
+
6
H
_
or HO
5a
935

On the basis of the transformations of 2-(4-oxo-3,4-dihydro-3-quinazolinyl)-2-(tetrahydro-2-furan-
ylidene)acetonitrile 1a it can be assumed that the intermediate product in this chain is the product 6 (produced
by the action of the alkalis on the derivative 1a), which can then split with the formation of the acetonitrile 5a.
The last transformation can be realized by heating an alcohol solution of compound 6 in the presence of an acid
or a base.
The structure of the product 6 was confirmed by data from the 1H NMR and IR spectra. In the 1H NMR
spectra in the region of 7.4-8.0 ppm there are signals for the protons of the quinazoline ring. In the downfield
region there are broad signals for two protons exchanging with the D2O: at 12 ppm for the 1-NH proton and at
14 ppm for the 3-NH proton (forming an intramolecular hydrogen bond with the C=O group of the acyl residue).
The signals for the protons of the methylene groups of the acyl fragment appear in the region of 1.7-3.5 ppm.
The H-8 proton of the quinazoline undergoes a paramagnetic shift (compared with the value of the latter for
compound 1a) and is observed in the form of a significantly broadened signal, possibly indicating the presence
of exchange interaction with the 1-NH proton, the signal of which is broader than the signal of the 3-NH proton.
In the IR spectra there is an absorption band for the C=O group of the quinazoline ring at 1690 cm−1 and
at 1645 cm−1 there is a band for the conjugated C=O group of the acyl fragment of the molecule taking part in
the formation of a hydrogen bond. The stretching vibrations of the conjugated C≡N group are observed at 2210
cm−1. Absorption in the region of 3400-2900 cm−1 is due to the NH bonds of the quinazolinone ring and the OH
group.
1
The structure of compounds 5a,b was confirmed by data from the H NMR spectra, IR spectra, and
elemental analysis, which fully agree with data for the previously obtained compounds [9, 10]. There was no
melting point depression in a mixed melting test with compounds 5a,b and the previously obtained compounds
[9, 10].
Thus, it was established as a result of the investigations that when alcohol solutions of 2-hetaryl-
2-(tetrahydro-2-furanylidene)acetonitriles are heated in the presence of secondary amines or acids the furan
fragment is split and subsequently eliminated, leading to the formation of the respective 2-hetarylacetonitriles.
EXPERIMENTAL
The IR spectra were recorded on a Perkin-Elmer Spectrum BX instrument (for compound 5a on a
Unicam SP 3-300 Pye instrument) in DMSO-d6 with TMS as internal standard. The reactions and the purity of
the products were monitored by TLC on Silufol UV-254 plates in the 9:1 chloroform–methanol system. The
melting points were measured on small-scale heater bench of the Boetius type with the VEB Analytik PHMK
observation device.
3-(4-Methoxy)-2-(4-oxo-3,4-dihydro-2-quinazolinyl)-
and
2-(1H-Benzo[d]imidazol-2-yl)-3-(4-
methoxy)- acrylonitriles 4a and 4b. To a mixture of the compound 1a,b (1.2 mmol) and aldehyde 2 (0.18 g,
1.3 mmol) in 2-propanol (10 ml) we added 3-4 drops of pyrrolidine (or 2-3 drops of hydrochloric acid). The
mixture was heated for 1-2 h until the initial compound 1 had disappeared (according to TLC). The pH of the
reaction mixture was then brought to 7. The precipitate was filtered off, washed with water and with alcohol,
and dried. A small quantity of the product 4a,b can be isolated from the mother liquor by adding 5-10 ml of
water.
Compound 4a. The yield 78%; mp 293-295°C (mp 293-295°C [7]). IR spectrum, ν, cm−1: 3440 (NH),
2224 (C≡N), 1675 (С=O). 1H NMR spectrum, δ, ppm (J, Hz): 3.88 (3Н, s, 4-СН3O); 7.19 (2Н, d, 3J = 8.5, Н-3,5
Аr); 7.56 (1H, t, 3J = 8.0, Н-6); 7.72 (1H, d, 3J = 8.0, Н-8); 7.86 (1H, t, 3J = 8.0, Н-7); 8.02 (2Н, d, 3J = 8.5, Н-
3
2,6 Аr); 8.15 (1H, d, J = 8.0, Н-5); 8.43 (1H, s, =CH─Ph); 12.55 (1H, br. s, NH). Found, %: N 13.71.
C18H13N3O2. Calculated, %: N 13.85.
936

1
Compound 4b. The yield 84%; mp 223-225°C. IR spectrum, ν, cm−1: 3434 (NH), 2224 (C≡N). H
3
NMR spectrum, δ, ppm (J, Hz): 3.88 (3Н, s, 4-СН3O); 7.17 (2Н, d, J = 8.5, Н-3,5 Аг); 7.25 (2Н, m, Н-5,6);
7.61 (2Н, m, Н-4,7); 8.01 (2Н, d, 3J = 8.5, Н-2,6 Аr); 8.28 (1H, s, =CH─Ph); 13.00 (1H, br. s, NH). Found, %:
N 15.30. C17H13N3O. Calculated, %: N 15.26.
2-(4-Oxo-3,4-dihydro-2-quinazolinyl)- and 2-(1H-Benzo[d]imidazol-2-yl)acetonitriles 5a and 5b.
To compound 1a,b (1.2 mmol) in 2-propanol (10 ml) we added 3-4 drops of pyrrolidine (or 2-3 drops of
hydrochloric acid). The mixture was heated for 1-2 h until the initial compound 1 had disappeared according to
TLC. The pH of the reaction mixture was then brought to 7. The precipitate was filtered off, washed with water,
and dried. A small quantity of the product 5a,b can be isolated from the mother solution by adding 5-10 ml of
water. The yield of compound 5a was 92%, and the yield of compound 5b was 87%.
(2E)-6-Hydroxy-2-(4-methylene-3,4-dihydro-2(1H)-quinazylidene)-3-oxohexanenitrile (6). To a
suspension of compound 1a (0.51 g, 2 mmol) in ethanol (or 2-propanol) (20 ml) we added 1.04 ml of a 10%
aqueous solution of NaOH. The mixture was boiled for 2-3 h while the end of the reaction was monitored by
chromatography. The reaction mixture was cooled, and the pH of the mixture was brought to 7. The precipitate
was filtered off, washed with water and with alcohol, and dried. A small quantity of the product 6 can be
isolated from the mother solution by adding 10 ml of water. The yield 88%; mp 221°C. IR spectrum, ν, cm−1:
2900-3400 (NH, ОН), 2210 (C≡N), 1690 (NHС=О), 1645 (С=О), 1600 (C=CCN). 1H NMR spectrum, δ, ppm (J,
3
3
Hz): 1.75 (2Н, m, CH2CH2CH2); 2.68 (2Н, t, J = 7.6, СОСН2); 3.44 (2Н, t, J = 6.3, СН2ОН); 4.31 (1Н, br. s,
ОН); 7.38 (1Н, t, 3J = 7.8, Н-6); 7.74 (1Н, t, 3J = 7.8, Н-7); 7.8 (1Н, br. s, Н-8); 8.0 (1Н, d, 3J = 7.8, Н-5); 11.56
(1Н, br. s, 1-NH); 13.97 (1H, br. s, 3-NH). Found, %: N 15.35. С14Н13N3O3. Calculated, %: N 15.49.
2-(4-Oxo-3,4-dihydro-2-quinazolinyl)acetonitrile (5a). To compound 6 (0.43 g, 1.6 mmol) in
2-propanol (15 ml) we added 30% aqueous solution of NaOH (0.2 ml) (or 2-3 drops of hydrochloric acid). The
mixture was heated for 1-2 h until the initial compound 6 had disappeared according to TLC. The pH of the
reaction mixture was then brought to 7. The precipitate was filtered off, washed with water and with alcohol,
and dried. A small quantity of the product 6 can be isolated from the mother solution by adding 10 ml of water,
The yield was 83%.
REFERENCES
1.
2.
Yu. M. Volovenko, O. V. Khilya, and T. A. Volovnenko, Khim. Geterotsikl. Soedin., 439 (2003).
[Chem. Heterocycl. Comp., 39, 394 (2003)].
Yu. М. Volovenko, О. V. Khilya, and Т. А. Volovnenko, in: Abstracts of SFC (Société Française de
Chimie) ''Eurochem Toulouse 2002'', 2002, CD, p. 1.
3.
4.
O. V. Khilya, Thesis Cand. Chem. Sci. [in Russian], Kiev (2003).
Yu. M. Volovenko, O. V. Khilya, and T. A. Volovnenko, in: V. G. Kartsev (editor), Oxygen- and
Sulfur-Containing Heterocycles. Proceedings of Second International Conference "Chemistry and
Biological Activity of Oxygen- and Sulfur-Containing Heterocycles" [in Russian], IBS Press, Moscow
(2003), Vol. 1, p. 217.
5.
6.
N. B. Marchenko and V. G. Granik, Khim. Geterotsikl. Soedin., 68 (1982). [Chem. Heterocycl. Comp.,
18, 58 (1982)].
L. V. Ershov and V. G. Granik, Khim. Geterotsikl. Soedin., 929 (1985). [Chem. Heterocycl. Comp., 21,
771 (1985)].
7.
8.
9.
M. A. Abdel, H. A. Aziz, S. M. Daboun, and Abdel Gawad, J. Prakt. Chem., 332, 610 (1990).
G. Wittig and H. Hartmann, Ber., 72, 1387 (1939).
Yu. M. Volovenko, O. V. Khilya, T. A. Volovnenko, and T. V. Shokol, Khim. Geterotsikl. Soedin., 350
(2002). [Chem. Heterocycl. Comp., 38, 314 (2002)].
10.
J. Buchi, H. Zwicky, and A. Aebi, Arch. Pharm., 293, 758 (1960).
937